Paclitaxel synthesis from precursor compounds and methods of producing the same

ABSTRACT

An efficient protocol for the synthesis of taxol, taxol analogs and their intermediates is described. The process incudes the attachment of the taxol A-ring side chain to baccatin III and for the synthesis of taxol and taxol analogs with variable A-ring side chain structures. A rapid and highly efficient esterification of O-protected isoserine and 3-phenylisoserine acids having N-benzyoloxycarbonyl groups to the C-13 hydroxyl of 7-O-protected baccatin III is followed by a deprotection-acylation sequence to make taxol, celphalomanninne and various analogs, including photoaffinity labeling candidates.

RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.08/357,507, now U.S. Pat. No. 5,770,745, filed Dec. 15, 1994, which is acontinuation of application Ser. No. 08/015,095 filed Feb. 5, 1993, nowabandoned.

FIELD OF THE INVENTION

This invention generally relates to the synthesis of paclitaxel fromprecursor compounds. More particularly, though, this invention concernsthe semi-synthesis of taxol using a protected baccatin III backbonewhich is esterified with a suitably protected side chain acid to producean intermediate that may thereafter be acylated and deprotected toproduce paclitaxel.

BACKGROUND OF THE INVENTION

The chemical compound referred to in the literature as taxol, and morerecently "paclitaxel", has received increasing attention in thescientific and medical community due to its demonstration of anti-tumoractivity. Paclitaxel has been approved for the chemotherapeutictreatment of several different varieties of tumors, and the clinicaltrials indicate that paclitaxel promises a broad range of potentanti-leukemic and tumor-inhibiting activity. As is known, paclitaxel isa naturally occurring taxane diterpenoid having the formula andnumbering system as follows: ##STR1##

While the paclitaxel molecule is found in several species of yew (genusTaxus, family Taxaceae), the concentration of this compound is very low.Moreover, these evergreens are slow-growing. Thus, a danger exists thatthe increasing use of paclitaxel as an effective anti-cancer agent willdeplete natural resources in the form of the yew trees. Indeed, whilethe bark of the yew trees typically exhibits the highest concentrationof paclitaxel, the production of 1 kilogram of paclitaxel requiresapproximately 16,000 pounds of bark. Thus, the long term prospects forthe availability of paclitaxel through isolation are discouraging.

The paclitaxel compound, of course, is built upon the baccatin IIIbackbone, and there are a variety of other taxane compounds, such asbaccatin III, cephalomanine, 10-deacetylbaccatin III, etc., some whichare more readily extracted in higher yields from the yew tree. Indeed, arelatively high concentration of 10-deacetylbaccatin III can beextracted from the leaves of the yew as a renewable resource. Typically,however, these other taxane compounds present in the yew tree do notexhibit the degree of anti-tumor activity shown by the paclitaxelcompound.

Since the paclitaxel compound appears so promising as a chemotherapeuticagent, organic chemists have spent substantial time and resources inattempting to synthesize the paclitaxel molecule. A more promising routeto the creation of significant quantities of the paclitaxel compound hasbeen proposed by the semi-synthesis of paclitaxel by the attachment ofthe A-ring side chain to the C-13 position of the naturally occurringbaccatin III backbone derived from the various taxanes present in theyew. See, Denis et al, a "Highly Efficient, Practical Approach toNatural Taxol", Journal of the American Chemical Society, page 5917(1988). In this article, the partial synthesis of paclitaxel from10-deacetylbaccatin III is described.

The most straightforward implementation of partial synthesis ofpaclitaxel requires convenient access to chiral, non-racemic side chainand derivatives, an abundant natural source of baccatin III or closelyrelated diterpenoid substances, and an effective means of joining thetwo. Of particular interest then is the condensation of baccatin III or10-deacetylbaccatin III with the paclitaxel A-ring side chain. However,the esterification of these two units is difficult because of thehindered C-13 hydroxyl of baccatin III located within the concave regionof the hemispherical taxane skeleton. For example, Greene andGueritte-Voegelein reported only a 50% conversion after 100 hours in onepartial synthesis of paclitaxel. J. Am. Chem. Soc., 1988, 110, 5917.

In U.S. Pat. No. 4,929,011 issued May 8, 1990 to Denis et al entitled"Process for Preparing Taxol", the semi-synthesis of paclitaxel from thecondensation of a (2R,3S) side chain acid of the general formula:##STR2## wherein P₁ is a hydroxy protecting group with a taxanederivative of the general formula of: ##STR3## wherein P₂ is a hydroxyprotecting group is described wherein the condensation product issubsequently processed to remove the P₁ and P₂ protecting groups. InDenis et al, the (2R, 3S) 3-phenylisoserine derivative, with theexception of the P₁ protecting group, is the A-ring side chain for thepaclitaxel molecule. The P₂ protecting group on the baccatin IIIbackbone is protected by, for example, a trimethylsilyl or atrialkylsilyl radical.

An alternative semi-synthesis of paclitaxel is described in co-pendingU.S. patent application Ser. No. 08/357,507 to Swindell et al. Thisapplication discloses semi-synthesis of paclitaxel from a baccatin IIIbackbone by the condensation with a side chain having the generalformula: ##STR4## wherein R₁ is alkyl, olefinic or aromatic or PhCH₂ andP₁ is a hydroxyl protecting group

The side chain in Swindell et al is distinct from the side chainattachment used in Denis et al, above, in that the nitrogen is protectedas a carbamate. Preferably, the A-ring side chain is benzyloxycarbonyl(CBZ) protected. After esterification, the CBZ protecting group isremoved and replaced by PhCO to lead to paclitaxel. This processgenerated higher yields than that described in Denis et al. In Swindellet al, Ser. No. 08/357,507, the preferred masking groups were selectedto be trichloroethoxymethyl or trichloroethoxycarbonyl. Benzyloxymethyl(BOM) was, however, disclosed as a possible side chain hydroxlprotecting group for the 3-phenylisoserine side chain, but, according tothe processes described therein, the BOM protecting group could not beremoved from the more encumbered C-2' hydroxyl in the attached3-phenylisoserine side chain. The use of the BOM protected side chainwas not extensively investigated, for this reason.

U.S. Pat. No. 4,924,012, issued May 8, 1990 to Colin et al discloses aprocess for preparing derivatives of baccatin III and of10-deacetylbaccatin III, by condensation of an acid with a derivative ofa baccatin III or of 10-deacetylbaccatin III, with the subsequentremoval of protecting groups by hydrogen. Several syntheses of TAXOTERE®(Registered to Rhone-Poulenc Sante) and related compounds have beenreported in the Journal of Organic Chemistry: 1986, 51, 46; 1990, 55,1957; 1991, 56, 1681; 1991, 56, 6939; 1992, 57, 4320; 1992, 57, 6387;and 993, 58, 255; also, U.S. Pat. No. 5,015,744 issued May 14, 1991 toHolton describes such a synthesis.

Despite the advances made in the semi-synthesis of the paclitaxelmolecule in the above described processes, there remains a need for moreefficient protocols for the synthesis of paclitaxel in order to increaseefficiencies in yields and production rates. There remains such a needfor semi-synthesis that may be implemented into commercial processes.There is a further need for efficient protocols for the synthesis ofpaclitaxel analogs, intermediates and various A-ring side chainstructures.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a new intermediatecompound useful for the semi-synthesis of paclitaxel.

It is another object of the present invention to provide a new anduseful process for the production of intermediate compounds that may beused for the semi-synthesis of paclitaxel.

Another object of the present invention is to provide a precursor and aproduction method therefor which may be used in the efficient and costeffective semi-synthesis of paclitaxel.

According to the present invention, then, a paclitaxel intermediatecompound is provided in the present invention having the generalformula: ##STR5## wherein P₁ is a hydrogenatable benzyl protectinggroup. Preferably, this hydrogenatable benzyl protecting group isselected from a group consisting of benzyloxymethyl and benzyl.

The present invention also is directed to a process for a preparation ofthe above described paclitaxel intermediate by the condensation of N-CBZprotected C-2' hydroxyl-benzyl protected (2R,3S)-3-phenylisoserine sidechain with C-7 TES protected baccatin III. This condensation ispreferably conducted in the presence of a dialkyl carbodiimide which maypreferably be selected from a group consisting ofdiisopropylcarbodiimide and dicyclohexylcarbodiimide. Preferably, whenthe dialkylcarbodiimide is diisopropylcarbodiimide the condensation isconducted in the presence of dimethylamino pyridine (DMAP) in a toluenesolution. The condensation is conducted at a temperature of about 80° C.for a time interval of three to five hours. The condensation may also beconducted in the presence of DMAP and the condensation product rinsedwith either ethyl ether or methyl t-butyl ether. Thereafter, thecombined organics may be washed with 5% hydrochloric acid, water andbrine. The organic phase may be separated, dried and reduced undervacuum with the resulting residue dissolved in ethyl acetate:hexane andeluded over a silica gel plug. The eluant may then be reduced to thedesired coupled product.

These and other objects of the present invention will become morereadily appreciated and understood from a consideration of the followingdetailed description of the exemplary embodiments.

DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS

The present disclosure is broadly directed to a chemical process for theefficient production of paclitaxel, intermediates and precursorstherefor. More specifically the present invention concerns thesemi-synthesis of paclitaxel by esterifying (suitably protected)3-phenylisoserine acids having hydrogenatable benzyl protecting groupsat C-2' to the C-13 hydroxyl of 7-O-protected baccatin III. Moreparticularly, the present invention utilizes triethylsilyl (TES)protection at the C-7 site. The general process described hereininvolves the production of C-7 TES baccatin III, the production of thesuitably protected 3-phenylisoserine acid having a hydrogenatable benzylprotecting group at C-2', the condensation of the two compounds, and thesubsequent deprotection and acylation of the condensation product toform paclitaxel.

A. Production of C-7 TES Protected Baccatin III

As a starting point in the semi-synthesis of paclitaxel according to theexemplary embodiment of the present invention, it is necessary toprovide the baccatin III backbone onto which the paclitaxel-analog sidechain may be attached. According to the present invention, it ispreferred that this backbone be in the form of the basic baccatin IIIbackbone that is protected at the C-7 site with a TES protecting group.Particularly, it is desired to provide a reaction intermediate of theformula: ##STR6## The compound of formula 5 may hereinafter be referredas TES-protected baccatin III, and its preparation may be accomplishedby the various routes described in the literature.

One such route is described in Denis et al, "A highly Efficient,Practical Approach to Natural Taxol", Journal of the American ChemicalSociety, p. 5917 (1988). Here, 10-deacetylbaccatin III is firstconverted to C-7 TES protected 10-deacetylbaccatin III and subsequentlythe C-7 TES protected 10-deacetylbaccatin III is converted to C-7 TESprotected baccatin III by the acylation of the compound at the C-10location. C-7 TES protected 10-deacetylbaccatin III is achievedaccording to the following reaction: ##STR7## Here, 10-deacetylbaccatinIII is reacted with a large excess of TES-Cl and pyridine to produce C-7TES protected 10-deacetylbaccatin III. The product is next acylatedutilizing an excess of acetyl chloride and pyridine to produce C-7 TESbaccatin III.

Alternatively, C-7 TES protected baccatin III may be efficientlyproduced according to the procedure described in Kant et al "A ChemoSelective Approach To Functionalize the C-10 Position of10-deacetylbaccatin III Synthesis and Biological Properties of NovelC-10 Taxol® Analogs", Tetrahedron Letters, Vol. 35, No. 31, TP5543-5546(1994). As described in this article, C-7 TES protected C-10 hydroxybaccatin III may be obtained according to the reaction: ##STR8## Here,imidazole is added while stirring to a solution of 10-deacetylbaccatinIII in dimethylformamide (DMF) under a nitrogen atmosphere.Triethylsilyl chloride (TES-Cl) is then added dropwise over a period ofapproximately five minutes. The resulting solution is stirred orotherwise moderately agitated for three hours after which the mixture isquenched with water and extracted with two portions of either diethylether or methyl t-butyl ether, and the combined organics are mixed andwashed with four portions of water and one portion brine. The organicand aqueous layers are then separated and the organic layer is dried andreduced under vacuum to form a crude solid. This crude solid is thenrecrystallized from ethyl acetate/hexane to produce C-10 hydroxy C-7 TESbaccatin III.

Next, the C-10 hydroxy C-7 TES baccatin III is acylated to produce C-7TES baccatin III according to the following reaction: ##STR9## The C-10hydroxy C-7 TES baccatin III is dissolved in anhydrous tetrahydrofuran(THF) and the solution is cooled under a nitrogen atmosphere to atemperature of less than -20° C. n-Butyl lithium (1.6 M in hexane) isadded dropwise, and the mixture is stirred at the reduced temperaturefor approximately five minutes. Acetyl chloride is then added dropwiseand the mixture warmed to 0° C. over an interval of five minutes andthen stirred at that temperature for approximately one hour. The mixtureis then quenched with water and reduced under vacuum, after which theresidue is taken up in ethyl acetate and washed once with water and thenbrine. The organic layer may then be dried and reduced under vacuum, andthe residue recrystallized with ethyl acetate/hexane to yield C-7 TESbaccatin III as a white solid. The selected electrophile is AcCl. Ayield of 90% was reported in this article.

Alternatively, of course, the C-7 TES protected baccatin III can be madedirectly from baccatin III instead of the route described above for theconversion from 10-deacetylbaccatin III.

B. Production of N-carbamate Protected C-2' hydroxyl-Benzyl Protected(2R,3S) 3-Phenyl Isoserine A-ring Side Chain

The second precursor necessary for the semi-synthesis of paclitaxelaccording to the present invention is the N-carbamate protected C-2'hydroxylbenzyl protected (2R,3S) phenyl isoserine side chain having thegeneral formula: ##STR10## wherein R₁ is an alkyl, olefinic, or aromaticPhCH₂ and P₁ is a hydrogenatable benzyl protecting group

The preferred hydrogenatable benzyl protecting group is abenzyloxymethyl (BOM) protecting group although other hydrogenatablebenzyl protecting groups, including benzyl, are believed suitable aswell. The preferred N-carbamate protecting group is benzyloxycarbonyl(CBZ). The starting compound to produce the desired side chain is(2R,3S)-3-phenylisoserine ethyl ester to produce N-CBZ protected(2R,3S)-3-phenylisoserine ethyl ester according to the reaction:##STR11## Here, (2R,3S)-3-phenylisoserine ethyl ester was alternativelydissolved in either equal parts diethyl ether:water or equal partsmethyl t-butyl ether:water and the solution was cooled to 0° C. Thesodium carbonate was then added to the solution and benzylchloroformatewas added dropwise over an interval of about five minutes and theresulting mixture stirred at 0° C. for approximately one hour. After theone hour stirring, the solution was then poured into water and extractedwith methylene chloride or ethyl acetate, as desired. The organic layeris separated, dried and reduced under vacuum to residue. The residue wasthen recrystallized from ethyl acetate:hexane to result in N-CBZprotected (2R,3S)-3-phenylisoserine ethyl ester having the formula:##STR12##

The N-CBZ protected (2R,3S)-3-phenylisoserine ethyl ester was nextprotected by the hydrogenatable benzyl protecting group, in severalways. For example, one route to the desired hydrogenatable benzylprotected side chain is as follows: ##STR13## Here, the CBZ protected(2R,3S)-3-phenylisoserine ethyl ester is dissolved in anhydrous THFunder a nitrogen atmosphere and cooled to a reduced temperature such as-40° C. or -78° C., for example, in a dry ice/acetone bath followed bythe dropwise addition of an alkylithium agent, such as n-butyl lithium,although it is desirable that the alkylithium agent be a straight chainalkyl. In any event, the reaction is best done at a temperature nogreater than 0° C. The resulting mixture was stirred for about tenminutes. Benzyloxymethyl chloride (BOM-Cl) was then added dropwise overan interval of about five minutes and the mixture stirred forapproximately two to five hours at the reduced temperature. Thereafter,the solution was warmed to -0° C. and quenched with water. The resultingmixture is reduced under vacuum to residue, and this residue isthereafter taken up in ethyl acetate and washed with water and brine.The organic layer may then be dried and reduced under vacuum and theresidue recrystallized from ethyl acetate:hexane or chromotographed withethyl acetate:hexane to give the compound: ##STR14##

Another route in the production of the compound according to formula 8is accomplished by dissolving the compound N-CBZ(2R,3S)-3-phenylisoserine ethyl ester in anhydrous methylene chloride.Thereafter, a tertiary amine base, such as diisopropylethylamine, isadded along with BOM-Cl and the mix is refluxed for twenty-four hours.While this reaction route will produce N-CBZ protected C-2' hydroxyl!protected (2R,3S)-3-phenylisoserine ethyl ester, the reaction proceedsmuch more slowly than the preferred route, discussed above.

In either instance, the resulting protected (2R,3S)-3-phenylisoserineethyl ester compound of formula 8 may simply be converted to the N-CBZprotected C-2' O-BOM-protected (2R,3S) phenylisoserine intermediatehydroxyl by the reaction: ##STR15##

Here, the protected (2R,3S)-3-phenylisoserine ethyl ester is dissolvedin ethanol/water (ratio 8:1). Lithium hydroxide (or other suitablealkali hydroxide) is added to the solution and the resulting mixturestirred for approximately three hours in order to saponify the compound.The mixture is then acidified (1 N HCl) and extracted with ethylacetate. The resulting organic layer is separated, dried and reducedunder vacuum. The residue acid is then isolated for use without furtherpurification. This produces the desired side chain having the generalformula: ##STR16##

Benzyl itself is another example of a hydrogenatable benzyl protectinggroup that may be used instead of BOM. The compound of the formula:##STR17## was therefore produced as above with the substitution ofbenzyl bromide for BOM-Cl in Reaction V according to the reaction##STR18## Here, the CBZ protected (2R,3S)-3-phenylisoserine ethyl esteris dissolved in anhydrous THF under a nitrogen atmosphere and cooled toa reduced temperature such as -40° C. or -78° C., for example, in a dryice/acetone bath followed by the dropwise addition of an alkylithiumalthough it is desirable that the alkylithium agent be a straight chainalkyl. the resulting mixture was stirred for about ten minutes. Benzylbromide (BnBr) was then added dropwise over an interval of about fiveminutes and the mixture stirred for approximately two to five hours atthe reduced temperature. Thereafter, the solution was warmed to -0° C.and quenched with water. The resulting mixture is reduced under vacuumto residue, and this residue is thereafter taken up in ethyl acetate andwashed with water and brine. The organic layer may then be dried andreduced under vacuum and the residue recrystallized from ethylacetate:hexane or chromatographed with ethyl acetate:hexane to give thecompound of Formula 10.

Alternatively, the compound of Formula 10 may be obtained according tothe reaction: ##STR19## Here, to a stirred solution of NaH in anhydrousDMF under N₂ was added Formula 7 dissolved in DMF over five minutes. Themixture was then stirred at 0° C. for one half hour. After which timebenzyl bromide (1.1 equivalents) was added dropwise over five minutesand the reaction stirred for two hours. The mixture was then quenchedwith H₂ O. Thereafter, a selected one of diethylether and methyl t-butylwas added. The organic layer was then washed with four portions of H₂ O,brine, and then dried and reduced under vacuum to produce Formula 10.Formula 10 may then be readily converted into: ##STR20## by the processof Reaction VI, above.

C. Condensation of C-7 TES Protected Baccatin III and the Side Chain

The side chain designated above as Formula 9 (or Formula 11) as well asthe C-7 TES protected baccatin III may now be condensed, again by avariety of routes. By way of example, this condensation may proceed inthe presence of a diisopropylcarbodiimide and dimethylamino pyridine(DMAP) in toluene at 80° C. according to the reaction: ##STR21## Here,C-7 TES protected baccatin III (1 equivalent) and the acid side chain ofFormula 9 (6 equivalents) are dissolved in toluene. To this mixture DMAP(2 equivalents) and diisopropylcarbodiimide (6 equivalents) are added,and the resulting mixture heated at 80° C. for three to five hours. Itshould be noted, however, that other dialkyl carbodiimides may besubstituted for the diisopropylcarbodiimide, with one example beingdicyclohexylcarbodiimide (DCC). Next, the solution was cooled to 0° C.and held at this temperature for twenty-four hours. After this time itwas filtered and the residue rinsed with either ethyl ether or methylt-butyl ether. The combined organics were then washed with hydrochloricacid (5%), water and, finally, brine. The organic phase was separated,dried and reduced under vacuum. The resulting residue was then dissolvedin ethyl acetate:hexane and eluted over a silica gel plug. The eluent isthen reduced under vacuum to result in the compound: ##STR22##

D. Deprotections and Acylation to Form Paclitaxel

The compound according to the Formula 12 may now be converted intopaclitaxel by removing the CBZ protecting group and acylating the sidechain, removing the TES protecting group and removing the hydrogenatablebenzyl protecting group. Here, several convenient routes have been foundalthough in general, it is necessary to deprotect the C-7 site byremoving the TES protecting group prior to deprotecting the C-2' sitewith the hydrogenatable benzyl protecting group. If the TES protectinggroup is not removed first, it is believed difficult at best to removethe hydrogenatable protecting group in a later processing step.

In any event, the preferred route of producing paclitaxel is to firstremove the CBZ protecting group according to the reaction: ##STR23##Here, the coupled product of Formula 12 is dissolved in isopropanol towhich the Pearlman's catalyst is added. The resulting mixture is stirredunder one atmosphere of hydrogen for twenty-four hours. Thereafter, themixture is filtered through diatomaceous earth and reduced under vacuumto residue. The residue may then be taken up in ethyl acetate or tolueneand a tertiary amine base, such as triethylamine is added. Benzoylchloride was added dropwise, and the mixture stirred for two hours. Theresulting mixture was then washed with dilute NaHCO₃, water, and finallybrine. The resulting organic phase was then separated, dried and reducedunder vacuum to yield the CBZ deprotected/acylated compound: ##STR24##

Next, the compound of Formula 13 is deprotected at C-7 according to thereaction: ##STR25## Here, the compound of Formula 13 was dissolved inacetonitrile (CH₃ CN) at 0° C. Hydrofluoric acid (40% aqueous) was thenadded and the mixture stirred for ten hours while being held at 0° C.Thereafter, the mixture is diluted with ethyl acetate, saturated NaHCO₃,water and finally brine. The organic phase was separated, dried andreduced under vacuum to produce a deprotected product at the C-7position according to the formula: ##STR26##

Finally, the compound of Formula 14 is deprotected at C-2' to remove thehydrogenatable benzyl (BOM) protecting group and to liberate the C-2'hydroxy group thereby resulting in the desired paclitaxel. This isaccomplished according to the reaction: ##STR27##

Alternatively, the compound of Formula 12 may first be dissolved in CH₃CN at 0° C. and hydrofluoric acid (40% aqueous) added to deprotect thecompound at the C-7 site by removing the TES protecting group. Thisresults in a compound according to the formula: ##STR28## Next, the CBZprotecting group may be removed in a manner similar to that describedabove. Here, the compound of Formula 15 is dissolved in isopropanol andPearlman's catalyst was added along with trifluoroacetic acid (TFA) (1equivalent). The mixture was held at 40 psi of hydrogen at roomtemperature for approximately four days. This removes the CBZ protectinggroup and forms the C-2' BOM protected paclitaxel compound as a TFAsalt. The mixture was filtered through diatomaceous earth and reducedunder vacuum. Next, a base plus an acylating agent was added to theresidue. Specifically, the TFA salt of the C-2' BOM protected compoundwas dissolved in pyridine and either benzoyl chloride or benzoicanhydride was added. The resulting product is: ##STR29##

The compound of Formula 16 is dissolved in isopropyl alcohol and placedin a Parr bottle and Pearlman's catalyst was added. The mixture washydrogenated for twenty-four hours at 40 psi of hydrogen. Thereafter,the mixture was filtered through diatomaceous earth and the eluentreduced under vacuum. The residue may then be column chromatographedaccording to any desired technique or recrystallized from ethylacetate:hexane for the final paclitaxel product.

Accordingly, the present invention has been described with some degreeof particularity directed to the exemplary embodiment of the presentinvention. It should be appreciated, though, that the present inventionis defined by the following claims construed in light of the prior artso that modifications or changes may be made to the exemplary embodimentof the present invention without departing from the inventive conceptscontained herein.

We claim:
 1. A paclitaxel intermediate compound of the general formula:##STR30## wherein P₁ is a hydrogenatable benzyl protecting group.
 2. Apaclitaxel intermediate compound according to claim 1 wherein thehydrogenatable benzyl protecting group is selected from a groupconsisting of benzyloxymethyl and benzyl.
 3. A process for thepreparation of a paclitaxel intermediate compound having the generalformula: ##STR31## wherein P₁ is a hydrogenatable benzyl protectinggroup, the process comprising the condensation of a compound having theformula ##STR32## wherein P₁ is a hydrogenatable benzyl protecting groupwith C-7 TES-protected baccatin III of the formula ##STR33##
 4. Aprocess for the preparation of a paclitaxel intermediate compound havingthe general formula: wherein P₁ is a hydrogenatable benzyl protectinggroup, the process comprising the condensation of a compound having theformula ##STR34## wherein P₁ is a hydrogenatable benzyl protecting groupwith C-7 TES-protected baccatin III of the formula ##STR35## wherein thecondensation is conducted in the presence of a dialkyl carbodiimide anddimethylamino pyridine in toluene at a temperature of about 80° C. for atime interval of about three hours to about five hours.
 5. A processaccording to claim 4 wherein said dialkyl carbodiimide is selected froma group consisting of diisopropylcarbodiimide and dicyclohexylcarbodiimide.
 6. A process according to claim 5 wherein said dialkylcarbodiimide is diisopropylcarbodiimide.
 7. A process according to claim3 wherein the condensation is conducted in the presence of a dialkylcarbodiimide.
 8. A process according to claim 7 wherein said dialkylcarbodiimide is selected from a group consisting ofdiisopropylcarbodiimide and dicyclohexyl carbodiimide.
 9. A processaccording to claim 8 wherein said dialkyl carbodiimide isdiisopropylcarbodiimide and said condensation is conducted in thepresence of dimethylamino pyridine in toluene.
 10. A process accordingto claim 9 wherein the condensation is conducted at a temperature ofabout 80° C. for a time interval of three to five hours.